This Program Project on VWD in the US is directed at the molecular and clinical understanding of this disorder. There is a lack in understanding the genetic causes of "low or abnormal VWF" and the molecular mechanisms involved in the pathophysiology and biology. While a large number of individuals have low or abnormal VWF with abnormal bleeding symptoms, it is not scientifically clear if this is a "disease" or that VWF is a continuous risk-factor for bleeding. The general understanding by practicing physicians about this group of disorders is not optimal and how these patients should be evaluated and treated has been often unclear.. This PPG will primarily focus on type 1 VWD, but will include some type 2 VWD patients correlate clinical and laboratory abnormalities. We will determine if bleeding and low VWF are genetically linked to the VWF gene locus; and if not, what is the magnitude of other modifying genes on either the clinical or the laboratory phenotype. Project 1 will determine the clinical and laboratory phenotype of a large cohort of VWD patients with particular emphasis on type 1 and carriers of type 3 VWD. Selected type 2 variants will be studied to contrast their phenotypic penetrance, clinical penetrance, and as a relative validation of the bleeding score. Full laboratory phenotyping and full-length DNA VWF gene sequencing will be undertaken to characterize these patients and the impact of allelic inheritance within their family on bleeding and laboratory phenotype. The laboratory features, bleeding symptoms and scoring of a subgroup containing women who exhibit menorrhagia as a major symptom will be studied for bleeding score and laboratory VWF phenotyping Project 2 will define the mechanisms behind the clinical and laboratory phenotypes/genotypes identified in Project 1, 3, and 4. Project 3 will identify modifying genes that affect the level, survival, function, and clinical manifestations of abnormal VWF. This project will utilize large, well characterized families with VWD (identified in Project 1/Core A) to identify associations with areas of the human genome other than the VWF locus on Chromosome 12. Project 4 will explore abnormalities in an extended promoter region, splice-junction mutations, and specific VWF-haplotypes as causes of abnormal or low VWF. It will make use of samples collected through Core A in which coding region mutations of the VWF gene are not identified. This project will also further study non-linked VWD for other causes outside the VWF locus. These 4 projects will be supported by Core A for administrative support and patient acquisition and Core B Clinical Laboratory and Sequencing Core.